Otitis media (middle ear inflammation) is one of the most common childhood diseases. The prevalence, medical costs, and hearing related morbidity of otitis media (OM) are significant. Streptococcus pneumoniae (Spn) is one of the primary pathogens of OM. Despite advances that have been made in Spn OM research in the last decade, much more remains to be learned about the otological immunology for better understanding of the pathogenesis of OM. The long-term objectives of this proposal are to evaluate host-bacterial cell interrelationship with the purpose of developing strategies for blocking or immunizing against this interaction and thus preventing the development of OM. The focus of this new application is to explore the critical role of complement in the middle ear in host innate immunity against Spn. The specific aims proposed are based on strong evidence from the studies performed in a mouse model of systematic infection, which have demonstrated that both the classical and alternative pathways are required in host innate immunity against invasive Spn. Little information is available about the role of complement in the middle ear defense against otopathogens. The specific aims are to: 1. Assess the complement activation in the middle ear epithelium during Spn infection. 2. Define the role of the specific complement pathways in the middle ear defense against Spn using a complement deficient mouse model. 3. Evaluate the role of complement C3 in the middle ear against Spn with an antecedent influenza A virus infection in the chinchilla model of OM, and to examine the relevance of alteration of Spn gene expression in vivo to complement resistance of Spn. Otitis media (middle ear inflammation) is one of the most common childhood diseases. The prevalence, medical costs, and hearing related morbidity of otitis media (OM) are significant. This application is designed to study the critical role of complement in middle ear defense against Streptococcus pneumoniae (Spn) bacteria, the primary pathogen of middle ear infection to better understand the host immune response to this pathogen.